Hematologic malignancies encompass cancers affecting blood, bone marrow, and lymph nodes and are particularly affected by modulation of the immune system since immune system cells are derived from hematologic lineages. Although hematologic cancers have traditionally been treated with conventional drug therapies, such as alkylating and other DNA damaging compounds, it is increasingly becoming recognized that immune checkpoint regulators play critical roles in determining whether hematologic cancer cells are tolerated or attacked by the immune system (Wu et al. (2012) Int. J. Biol. Sci. 8:1420-1430; Nirschl and Drake (2013) Clin. Cancer Res., electronically published July 18; Ceeraz et al. (2013) Trends Immunol., electronically published August 13). However, immune checkpoint regulators, such as CTLA-4, PD-1, VISTA, B7-H2, B7-H3, PD-L1, B7-H4, B7-H6, 2B4, ICOS, HVEM, PD-L2, CD160, gp49B, PIR-B, KIR family receptors, TIM-1, TIM-3, TIM-4, LAG-3, BTLA, SIRPalpha (CD47), CD48, 2B4 (CD244), B7.1, B7.2, ILT-2, ILT-4, TIGIT, LAG-3, BTLA, A2aR and many more, negatively regulate immune response progression based on complex and combinatorial interactions between numerous inputs. While some progress has been made to determine which interventions at which particular nodes of the immune checkpoint regulatory system can be targeted for benefiting the treatment of hematologic cancers (Kearl et al. (2013) J. Immunol. 190:5620-5628; Hallett et al. (2011) Biol. Blood Marrow Transplant. 17:1133-1145; Pardoll et al. (2012) Nat. Rev. Cancer 12:252-264; Brahmer et al. (2012) N. Engl. J. Med. 366:2455-2465; Mocellin et al. (2013) Biochim. Biophys. Acta 1836:187-196; Topalian et al. (2012) N. Engl. J. Med. 366:2443-2454; and Wolchok et al. (2013) N. Engl. J. Med. 369:122-133), it is not currently possible to identify specific interactions having synergistic anti-cancer therapeutic efficacy. Accordingly, there is a great need in the art to define specific and synergistic combinations of immune checkpoint regulators useful for treating hematologic cancers.